, Volume 22, Issue 2, pp 79–94 | Cite as

Palmitoylethanolamide, a naturally occurring disease-modifying agent in neuropathic pain

  • Stephen D. Skaper
  • Laura Facci
  • Mariella Fusco
  • Maria Federica della Valle
  • Morena Zusso
  • Barbara Costa
  • Pietro Giusti


Persistent pain affects nearly half of all people seeking medical care in the US alone, and accounts for at least $80 billion worth of lost productivity each year. Among all types of chronic pain, neuropathic pain stands out: this is pain resulting from damage or disease of the somatosensory nervous system, and remains largely untreatable. With few available treatment options, neuropathic pain represents an area of significant and growing unmet medical need. Current treatment of peripheral neuropathic pain involves several drug classes, including opioids, gabapentinoids, antidepressants, antiepileptic drugs, local anesthetics and capsaicin. Even so, less than half of patients achieve partial relief. This review discusses a novel approach to neuropathic pain management, based on knowledge of: the role of glia and mast cells in pain and neuroinflammation; the body’s innate mechanisms to maintain cellular homeostasis when faced with external stressors provoking, for example, inflammation. The discovery that palmitoylethanolamide, a member of the N-acylethanolamine family which is produced from the lipid bilayer on-demand, is capable of exerting anti-allodynic and anti-hyperalgesic effects by down-modulating both microglial and mast cell activity has led to the application of this fatty acid amide in several clinical studies of neuropathic pain, with beneficial outcome and no indication of adverse effects at pharmacological doses. Collectively, the findings presented here propose that palmitoylethanolamide merits further consideration as a disease-modifying agent for controlling inflammatory responses and related chronic and neuropathic pain.


Neuropathic pain Mast cells Microglia Neuro-immune interaction Natural products Palmitoylethanolamide 



The authors wish to thank Gabriele Marcolongo for his valuable input in providing details of the micronization/ultra-micronization process for PEA, and the associated figures and data. L. Facci was supported by Fondazione CARIPARO “Progetto Dottorati di Ricerca” Anno 2009. This study was supported in part by MIUR, PON ‘Ricerca e Competitività 2007–2013’ project PON01_02512.

Conflict of interest

MF is an employee of Epitech Srl; MFdV is a scientific consultant for Innovet Italia Srl.


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Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Stephen D. Skaper
    • 1
  • Laura Facci
    • 1
  • Mariella Fusco
    • 2
  • Maria Federica della Valle
    • 3
  • Morena Zusso
    • 1
  • Barbara Costa
    • 4
  • Pietro Giusti
    • 1
  1. 1.Department of Pharmaceutical and Pharmacological SciencesUniversity of PaduaPaduaItaly
  2. 2.Epitech Group Srl, Scientific Information and Documentation CenterSaccolongoItaly
  3. 3.CeDIS (Scientific Information and Documentation Center), Innovet Italia SrlSaccolongoItaly
  4. 4.Department of Biotechnology and Bioscience, University of Milan-BicoccaMilanItaly

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